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Systematic identification of a nuclear receptor-enriched predictive signature for erastin-induced ferroptosis.

ABSTRACT: Erastin, a synthetic lethal compound against cancer expressing an oncogenic RAS, inhibits cystine/glutamate antiporters and causes ferroptosis. However, despite recent evidence for the mechanisms underlying ferroptosis, molecular biomarkers of erastin-dependent ferroptosis have not been identified. Here, we employed isogenic lung cancer cell models to show that a redox imbalance leads to glutathione depletion and ferroptosis. Subsequent transcriptome analysis of pan-cancer cell lines revealed that the activity of transcription factors, including NRF2 and AhR, serve as important markers of erastin resistance. Based on the integrated expression of genes in the nuclear receptor meta-pathway (NRM), we constructed an NRM model and validated its robustness using an independent pharmacogenomics dataset. The NRM model was further evaluated by sensitivity tests on nine cancer cell lines for which erastin sensitivities had not been determined. Our pharmacogenomics approach has the potential to pave the way for the efficient classification of patients for therapeutic intervention using erastin.

SUBMITTER: Kwon OS

PROVIDER: S-EPMC7519368 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Systematic identification of a nuclear receptor-enriched predictive signature for erastin-induced ferroptosis.

Kwon Ok-Seon OS Kwon Eun-Ji EJ Kong Hyeon-Joon HJ Choi Jeong-Yoon JY Kim Yun-Jeong YJ Lee Eun-Woo EW Kim Wankyu W Lee Haeseung H Cha Hyuk-Jin HJ

Redox biology 20200912

Erastin, a synthetic lethal compound against cancer expressing an oncogenic RAS, inhibits cystine/glutamate antiporters and causes ferroptosis. However, despite recent evidence for the mechanisms underlying ferroptosis, molecular biomarkers of erastin-dependent ferroptosis have not been identified. Here, we employed isogenic lung cancer cell models to show that a redox imbalance leads to glutathione depletion and ferroptosis. Subsequent transcriptome analysis of pan-cancer cell lines revealed th ...[more]

PMID: 32979793

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Project description:BackgroundFerroptosis has been proven to contribute to the progression of myocardial ischemia/reperfusion (I/R) injury and can be inhibited or promoted by ATF3. Short-chain fatty acids (SCFAs) have shown benefits in various cardiovascular diseases with anti-inflammatory and antioxidant effects. However, the impact of SCFAs on ferroptosis in ischemic-stimulated cardiomyocytes remains unknown. This study aimed to investigate the effect of SCFAs on cardiomyocyte ferroptosis, the expression of ATF3, and its potential upstream regulators.Methods and resultsThe expression of ATF3, ferroptosis pathway geneset (FPG), and geneset of potential regulators for ATF3 (GPRA, predicted by the PROMO database) was explored in the public human myocardial infarction single-cell RNA-seq (sma) dataset. Cardiomyocyte data was extracted from the dataset and re-clustered to explore the FPG, ATF3, and GPRA expression patterns in cardiomyocyte subclusters. A dose-dependent toxic experiment was run to detect the suitable dose for SCFA treatment. The erastin-induced ferroptosis model and hypoxia-reoxygenation (H/R) model (10 h of hypoxia followed by 6 h of reoxygenation) were adopted to assess the effect of SCFAs via the CCK8 assay. Gene expression was examined via RT-PCR and western blot. Ferroptosis markers, including lipid peroxides and Fe2+, were detected using the liperfluo and ferroOrange probes, respectively. In the sma dataset, upregulated ferroptosis pathway genes were mainly found in the infarction-stimulated cardiac cells (border zone and fibrotic zone), particularly the cardiomyocytes and adipocytes. The ATF3 and some of its potential transcription factors (VDR, EGR3, PAX5, and SP1) can be regulated by SCFA. SCFA can attenuate erastin-induced lipid peroxidation in cardiomyocytes. SCFA treatment can also reverse erastin-induced Fe2+ increase but may strengthen the Fe2+ in the H/R model. We also precisely defined a ferroptosis subcluster of cardiomyocytes (CM09) that highly expressed FPG, ATF3, and GPRA.ConclusionThe ATF3 and the ferroptosis pathway are elevated in cardiomyocytes of injury-related cardiac regions (border zone, ischemic zone, and fibrotic zone). SCFA can attenuate cardiomyocyte ferroptosis and regulate the expression of ATF3. Our study offers novel insights into the potential targets of SCFAs in the cardiovascular system.

Dataset Information

Systematic identification of a nuclear receptor-enriched predictive signature for erastin-induced ferroptosis.

Publications

Systematic identification of a nuclear receptor-enriched predictive signature for erastin-induced ferroptosis.

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